Pyrido-pyrazinyl compounds for treating acute myeloid leukemia
The present invention provides compounds having kinase inhibitory activity. Specifically, the present invention provides compounds having a structure represented by the following formula (II). The compound of the present invention has good inhibitory activity for a variety of kinases (e.g. ALK, AXL, EGFR, and FLT3), and therefore can be used for preparing a pharmaceutical composition for treating kinase activity-related diseases (e.g. acute myeloid leukemia, etc.).
1 . A compound as shown in the following formula II, or a pharmaceutically acceptable salt or deuterated product thereof:
wherein, X and Y are N, and Z is CH;
Ra is H, substituted or unsubstituted C 1 -C 6 alkyl;
U is chemical bond or —NH—; and when U is chemical bond, Rc is pyrrolidine;
Rc is selected from the group consisting of substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 carbocyclic ring, substituted or unsubstituted 3-8 membered heterocyclic ring containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted C 6 -C 10 aryl, and substituted or unsubstituted 5-12 membered heteroaromatic ring containing 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen;
Re is —NHR; wherein R is selected from the group consisting of H, substituted or unsubstituted C 1 -C 6 alkyl, and substituted or unsubstituted phenyl;
W is substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted 5-12 membered heteroaromatic ring containing 1-3 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen;
the W group is substituted by at least one group having the structure of -M-A, wherein M is selected from the group consisting of chemical bond, —CH 2 —;
A is selected from the group consisting of substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted 5-12 membered heteroaromatic ring containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, and substituted or unsubstituted C 3 -C 12 cycloalkyl;
wherein, in the definition of A, the substitution means substituted by one or more groups selected from group B consisting of H, halogen, cyano, hydroxyl, aldehyde, carboxyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted 3-12 membered heterocyclic ring containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted 5-12 membered heteroaromatic ring containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted-C 1 -C 6 alkyl-phenyl, substituted or unsubstituted C 3 -C 12 cycloalkyl, substituted or unsubstituted C 2 -C 10 acyl, substituted or unsubstituted C 2 -C 10 ester group, substituted or unsubstituted C 1 -C 6 amide, and substituted or unsubstituted C 1 -C 4 alkyl-S(O) 2 —, and in the group B, the substitution means substituted by one or more R groups;
wherein R is selected from the group consisting of H, halogen, cyano, amino, nitro, hydroxyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 12 cycloalkyl, substituted or unsubstituted C 2 -C 10 ester group;
unless otherwise specified, in the above formulae, the substitution means that the hydrogen atom on the corresponding group is replaced by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, amino, C 1 -C 6 amide, cyano, unsubstituted or halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl-amino, C 1 -C 12 alkylaminocarbonyl, unsubstituted or halogenated C 2 -C 10 acyl, and unsubstituted or halogenated C 1 -C 4 alkyl-S(O) 2 —.
2 . The compound of claim 1 , or the pharmaceutically acceptable salt or deuterated form thereof, wherein the compound has the structure as shown in formula Ila:
wherein, W is selected from the group consisting of a substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, and substituted or unsubstituted pyrazolyl; wherein in the definition of W, said substitution means substituted by one or more groups selected from A.
3 . The compound of claim 1 , or the pharmaceutically acceptable salt or deuterated form thereof, wherein W is a substituted or unsubstituted phenyl.
4 . The compound of claim 1 , or the pharmaceutically acceptable salt or deuterated form thereof, wherein W is a substituted or unsubstituted
5 . The compound of claim 1 , or the pharmaceutically acceptable salt or deuterated product thereof, wherein the compound has the structure as shown in formula III:
wherein, A is selected from the group consisting of substituted or unsubstituted 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted 5-12 membered heteroaromatic ring containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted C 6 aryl, and substituted or unsubstituted C 3 -C 12 cycloalkyl;
M is a chemical bond, or —CH 2 —.
6 . The compound of claim 5 , or the pharmaceutically acceptable salt or deuterated product thereof, wherein the compound has the structure as shown in the following formula:
wherein,
Rf is selected from the group consisting of H, halogen, cyano, amino, hydroxyl, C 1 -C 4 alkyl-S(O) 2 —, substituted or unsubstituted C 1 -C 6 alkyl, and substituted or unsubstituted C 1 -C 6 alkoxy;
t is 0, 1, 2, 3 or 4;
A is selected from the group consisting of substituted or unsubstituted 5-12 membered saturated ring, and substituted or unsubstituted C 6 -C 10 aryl; and A has at least one heteroatom selected from N and O.
7 . The compound of claim 5 , or the pharmaceutically acceptable salt or deuterated product thereof, wherein the compound has the structure as shown in the following formula:
wherein,
Rf is H;
t is 0, 1, 2, 3 or 4;
L is N;
A is selected from the group consisting of a substituted or unsubstituted 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, a substituted or unsubstituted C 3 -C 12 cycloalkyl, a substituted or unsubstituted 5-12 membered heteroaromatic ring containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, and a substituted or unsubstituted C 6 -C 10 aryl.
8 . The compound, or the pharmaceutically acceptable salt or deuterated product thereof of claim 5 , the compound has the structure as shown in the following formula IV:
wherein, A is substituted or unsubstituted 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen substituted or unsubstituted C 6 aryl;
M is a chemical bond;
B is substituted or unsubstituted 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen;
V is a chemical bond.
9 . The compound of claim 5 , or the pharmaceutically acceptable salt or deuterated product thereof, wherein A has at least one substituent G, and G is selected from the group consisting of amino, ═O, substituted or unsubstituted 4-7 membered heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, substituted or unsubstituted C 2 -C 10 ester, and substituted or unsubstituted C 1 -C 6 amide.
10 . The compound of claim 1 , or the pharmaceutically acceptable salt or deuterated product thereof of, wherein the compound is selected from the following compounds;
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11 . A pharmaceutical composition comprising an effective amount of one or more of the compound of claim 1 , or the pharmaceutically acceptable salt, racemate, R-isomer and S-isomer, stereoisomer or a tautomer thereof, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients and/or diluents.
12 . A method of treating or preventing a disease, the method comprising administering to the subject an effective amount of the compound of claim 1 , or the racemate, R-isomer, S-isomer or the pharmaceutically acceptable salt thereof; wherein the disease is selected from the group consisting of acute myeloid leukemia, neurofibroma type I, multiple myeloma, non-small cell lung cancer, liver cancer, hepatocellular carcinoma, cervical cancer, lymphoma, bone metastases, hormone refractory prostate cancer, hormone dependent prostate cancer, thyroid adenoma, medullary thyroid carcinoma, mesothelioma, glioblastoma, sphincter metastases, Merkel cell carcinoma, urogenital tract tumor, bladder cancer, papillary thyroid cancer, breast cancer, soft tissue sarcoma, glioma, neuroendocrine tumor, renal cell carcinoma, advanced solid tumor, undifferentiated astrocytic cell carcinoma, gastrointestinal stromal tumor, Hipper-Lindau syndrome, small cell lung cancer, pancreatic cancer, pancreatic endocrine carcinoma, central nervous system tumor, metastatic renal cancer, endometrioid carcinoma, endometrioid adenocarcinoma, lung cancer, colorectal cancer, ovarian cancer, rhabdomyosarcoma, melanoma, retinoblastoma, tumors of the central and peripheral nervous system, acute leukemia, chronic leukemia, cholangiocarcinoma, bronchiocarcinoma, esophageal cancer, testicular cancer, skin cancer, oral cancer, neuroblastoma, and anaplastic large cell lymphoma.
13 . A compound of the formula IV, or the pharmaceutically acceptable salts or deuterated products thereof,
wherein, X and Y are N, and Z is CH;
Ra is selected from the group consisting of H, and substituted or unsubstituted C 1 -C 6 alkyl;
U is —NH—;
Rc is selected from the group consisting of substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 carbocyclic ring, substituted or unsubstituted 3-8 membered heterocyclic ring containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted C 6 -C 10 aryl, and substituted or unsubstituted 5-12 membered heteroaromatic ring containing 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen;
Re is —NH 2 ;
W is substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted 5-12 membered heteroaromatic ring containing 1-3 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen;
the W group is substituted by at least one group having the structure of -M-A, wherein M is selected from the group consisting of chemical bond, —CH 2 —;
the A ring is selected from the group consisting of substituted or unsubstituted 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from oxygen, and substituted or unsubstituted C 6 aryl;
M is a chemical bond, —CH 2 —;
B ring is substituted or unsubstituted 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen; and in the group B, the substitution means substituted by one or more R groups;
wherein R is selected from the group consisting of H, halogen, cyano, amino, nitro, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C12 cycloalkyl, and substituted or unsubstituted C2-C10 ester group;
V is —CH 2 —;
unless otherwise specified, in the above formulae, the substitution means that the hydrogen atom on the corresponding group is replaced by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, amino, C 1 -C 6 amide, cyano, unsubstituted or halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl-amino, C 1 -C 12 alkylaminocarbonyl, unsubstituted or halogenated C 2 -C 10 acyl, and unsubstituted or halogenated C 1 -C 4 alkyl-S(O) 2 —.
14 . A compound selected from the group consisting of:
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